CZ288076B6 - Tricyclic amines and intermediates for preparing thereof - Google Patents

Abstract

In the present invention there are disclosed tricyclic amines of the general formula IV and salts thereof being usable for treating asthma. In the present invention there are also claimed intermediates for their preparation.

Description

Technical field

The pharmaceutically active tricyclic amines of the invention are useful as pharmaceuticals for the treatment of many diseases and injuries.

BACKGROUND OF THE INVENTION

International Publication WO92 / 025000-A shows that 2-phenylindole derivatives may be effective in the treatment of asthma, allergic diseases, thromboses and ischemia.

Journal J. Heterocyclic. Chem., 24, 425 (1987) discloses pyrrolopyrimidines wherein the amino groups on the pyridine backbone are free and unsubstituted, while the compounds of the invention are substituted aminopyrrolopyrimidines.

International publication WO91 / 04254 shows pyrrolo [2,3-d] pyrimidines wherein the groups substituted on the pyrrole ring are simple. In two of the positions, the group is -H, halogen or alkyl. In the third position is -H, alkyl or aralkyl.

International Publication WO93 / 20078 based on PCT / US93 / 02188 and International Publication WO96 / 26941 based on PCT7US96 / 02397 disclose various pyrimido [4,5-b] indoles having pharmaceutical use. The invention is based on international publications WO93 / 20078 and WO96 / 26941.

SUMMARY OF THE INVENTION

Tricyclic amines of formula IV are disclosed

wherein R m and R ₁₂ are linked to a nitrogen atom to which they are attached to form a heterocyclic ring selected from: 1-pyrrolidinyl, 1-piperidyl and 4-morpholinyl;

wherein R _{2 - 1} and R _{2 - 2} are linked to the nitrogen atom to which they are attached to form a heterocyclic ring selected from: 1-pyrrolidinyl, 1-piperidyl and 4-morpholinyl, provided that the heterocyclic ring R 1 - Ri_ ₂ is the same as R ₂ _i / _ ₂ R _2;

-1 kdenijelaž3;

where Rí_i is:

(1) -H (2) C 1 -C ₃ alkyl (3) -phenyl;

wherein R _{3 - 2} is (1) -H (2) -CH ₂ - [2-pyridyl], (3) -CH 2 -P-pyridyl], (4) -CH ₂ - [4-pyridyl], (5) -CHHCH (OH)] 4CH 2 -OH, (7) -CH 2 -COOH, (8) -OH, (9) -CH ₂ -CH ₂ -CH ₂ -CH ₂ -OH, (10) -CH ₂ -CH ₂ -CH ₂ -CO-OH, and wherein R _{3 and} R ₃ are linked to a nitrogen atom to which they are attached to form a heterocyclic ring selected from:

(1) 1-pyrrolidinyl, (2) 1-piperidyl, (3) 4-morpholinyl, (4) 2-hydroxy-1-pyrrolidinyl, (5) 3-hydroxy-1-pyrrolidinyl, (6) 1-prolyl and pharmaceutically acceptable salts thereof.

Also disclosed are (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9yl) acetic acid, t-butyl ester, (2,4-di-1-pyrrolidinyl-9H-pyrimido [ 4,5-b] indol-9-yl) acetic acid and its pharmaceutically acceptable salts as intermediates for the preparation of the tricyclic amines of formula IV according to the invention.

The tricyclic amines IV and their pharmaceutically acceptable salts V according to the invention are prepared by methods known to those skilled in the art from known starting compounds. The invention is tricyclic amines IV and their pharmaceutically acceptable salts V, not the chemical reactions required for their preparation.

The tricyclic amines IV of the invention can be prepared by the procedures previously reported in International Publications WO93 / 20078 and WO92 / 26941 and by the procedures in Schemes A-C. There are two 40 preferred processes for preparing the tricyclic amines IV of the invention. The first procedure utilizes the chemical reactions described in Schemes A and B. The second procedure utilizes the chemical reactions described in Schemes A and C. Both procedures utilize the two steps described in Scheme A.

The starting alcohol in Scheme A is known to those skilled in the art or can be readily prepared from known materials by procedures known to those skilled in the art. For example: J. Med. Chem., 38, 4161- (1995). The alcohol I is converted to a derivative having a leaving group by a procedure well known to those skilled in the art. Suitable leaving groups, -X 1, include methanesulfonate, p-toluenesulfonate and para -SO ₂ -O-NO ₂ , where 0 is phenyl. Preferably, X ₍ is methanesulfonate. The leaving group alcohol is then converted to the corresponding secondary amine III by treatment with sodium cyanide.

And trace-protected non-nucleophilic tertiary amine (in solvents such as DMF, DMSO or acetonitrile). Secondary amine III is the starting compound for two other processes. In a first process, CHART B, the secondary amine is alkylated with a molecular fragment which contains the side alkyl chain and the amide, - (CH ₂₎ n -CO-N (R3_i) (R3_2), where n _t is 1 to 3 thus directly gives the desired tricyclic amine IV. It is preferred that n 1 is 1. Pyrimido [4,5-b] indole is an amine base and as such forms pyrimido [4,5-b] indole salts V in a conventional manner, see Examples 2 to 6.

Alternatively, if it is equal to 1, it is also possible to alkylate the secondary amine III with t-butyl bromoacetate to form the butyl ester VI. The butyl ester VI is then hydrolyzed in a known manner to the corresponding acid VII. The acid is then converted into the corresponding tricyclic amines IV or their salts V by known methods.

Preferably, the tricyclic amines IV are in the form of pharmaceutically acceptable salts, the pyrimido [4,5-b] indole salts V, and it is preferred that the salt is selected from the group consisting of hydrochloride, hydrobromide, maleate and methanesulfonate.

Tricyclic amines IV are useful for treating and preventing asthma (and reducing mucus production and secretion in the lungs); dermatitis of atopic, inflammatory, allergic or contact nature (and reduction of itching, lacrimation, sebum secretion and skin thickening that accompanies dermatitis); rhinitis of atopic, inflammatory or seasonal allergic nature (and reduction of itching, lacrimation, sebum secretion and mucous secretion of the nasal mucosa that accompany rhinitis); conjunctivitis, eyelid inflammation, corneal inflammation or a combination of atopic, allergic, seasonal or inflammatory character (and reduction of itchiness, lacrimation, sebum secretion and mucous secretion of the eyes and their parts that accompany conjunctivitis, eyelid inflammation, corneal inflammation or their combination).

Tricyclic amines IV are useful in treating and preventing asthma (and reducing mucus production and secretion in the lungs). In the treatment of excessive mucus and asthma secretion, tricyclic amines IV are administered orally, with the active ingredient IV and inhalation of a standard dose. In the treatment of excessive mucus secretion, the oral dose of tricyclic amines IV ranges from about 0.05 to 20 mg / kg / day. Frequency of administration one to four times a day. Oral administration of tricyclic amines IV to treat excessive mucus secretion takes several months or even years. The affected individuals may be given the drug several hours before the expected problem. Dose IV is in the range of about 0.05 to 20 mg / kg / day. The aerosol form of the medicament contains from about 0.01 to 1% tricyclic amines IV and is administered or used approximately four times a day, if necessary.

Tricyclic amines IV are also useful in the treatment and prevention of atopic, inflammatory, allergic or contact dermatitis (and the reduction of itchiness, lacrimation, sebum secretion and skin thickening that accompanies dermatitis). In the treatment of dermatitis and the associated signs and symptoms, tricyclic amines IV are administered orally in a standard dose and topically administered by various forms for oral administration (solutions, suspensions, creams, ointments, lotions, powders, gels or other recognizable mixtures) of tricyclic amines IV. from 0.01% to 20% of tricyclic amines IV relative to the drug matrix. The frequency of administration is one to four times a day. Oral and local administration of tricyclic amines IV to treat the symptoms and / or symptoms of dermatitis may take several months or even years. Susceptible individuals may administer the drug several hours before the expected problem. The dose of Compound IV is in the range of about 0.05 to 20 mg / kg / day.

Tricyclic amines IV are also useful in the treatment and prevention of rhinitis of atopic, inflammatory or seasonal allergic nature (and the reduction of itchiness, lacrimation, sebum secretion and mucous secretion of the nasal mucosa that accompany rhinitis). In the treatment of rhinitis and accompanying signs and symptoms. The tricyclic amines IV are administered orally in standard amounts and topically applied by various forms for topical administration (solutions, suspensions, creams, ointments, lotions, powders, gels or other recognizable mixtures) of tricyclic amines IV at a concentration of about 0.01% to 20% tricyclic amines IV relative to the drug matrix. The frequency of administration is one to four times

-3GB 288076 B6 per day. Oral and local administration of tricyclic amines IV to treat the symptoms and / or symptoms of rhinitis may take several months or even years. Susceptible individuals may administer the drug several hours before the expected problem. The dose of Compound IV is in the range of about 0.05 to 20 mg / kg / day.

Tricyclic amines IV are also useful in the treatment and prevention of conjunctivitis, eyelid inflammation, corneal inflammation, or a combination of atopic, allergic, seasonal or inflammatory (and itching, tearing, secretion of sebum, and mucous secretions of eyes and parts thereof that accompany inflammation) conjunctivitis, inflammation of the eyelids, inflammation of the cornea or a combination thereof). In the treatment of conjunctivitis, eyelid inflammation, corneal inflammation or a combination thereof and associated symptoms and symptoms. The tricyclic amines TV are administered orally in standard amounts and topically applied by various forms for topical administration (solutions, suspensions, creams, ointments, lotions, powders, gels or other recognizable mixtures) of tricyclic amines IV at a concentration of about 0.001% to 20% tricyclic amines IV with respect to the drug matrix. The frequency of administration is one to four times a day. Oral and local administration of tricyclic amines IV to treat the symptoms and / or symptoms of conjunctivitis, eyelid inflammation, corneal inflammation, or a combination thereof may take several months or even years. Susceptible individuals may administer the drug several hours before the expected problem. The dose of Compound IV is in the range of about 0.05 to 20 mg / kg / day.

The term treatment and prevention as used herein is widely used and includes both the treatment of pre-existing conditions and the prevention of these same conditions where possible, as is known to those skilled in the art. For example, tricyclic amines IV can be used to treat existing asthmatic conditions and prevent future asthmatic conditions; existing dermatitis and to prevent their development in the future; existing rhinitis and prevent it from occurring in the future; existing conjunctivitis, eyelid inflammation, corneal inflammation, or a combination thereof, and to prevent their development in the future.

The exact dose size and frequency of administration will depend upon the particular tricyclic amines IV used, the particular types of conditions being treated, the degree of advancement of the conditions being treated, the age, weight, general physical condition of the individual patient, further medication of the individual as The dosage can be more accurately determined by measuring the concentration of tricyclic amides IV in the patient's blood or, depending on the response of the patient, by improving the individual conditions being treated.

The definitions and explanations below are for the terms used throughout this document, description and claims.

I. Convention formulas and definition of variables

The number of carbon atoms of the various substituents can be determined by two methods. The first method uses the prefix of the entire variable name, such as "C1-C4", where "1" and "4" are boundaries representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a dash. For example, "C 1 -C 4 alkyl" represents an alkyl of one to four carbon atoms (includes its isomeric forms without particular designation as opposed to the form). Whenever this particular prefix is used, the prefix determines the total number of carbon atoms of the variable that is defined. Thus, C ₂ -C ₄ alkoxycarbonyl describes a CH ₃ - (CH 2) n O-CO- group, wherein n is zero, one or two. Using the second method, only the number of carbon atoms of each part of the variable is determined separately by enclosing the designation "Cj-Cj" in parentheses and placing immediately before (without the space) the part of the variable that is defined. According to this chosen convention, the designation (C 1 -C ₃ ) alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl, since "C 1 -C ₃ " gives information only on the number of carbon atoms in the alkoxy group. Similarly, although both C 2 -C 6 alkoxyalkyl and (C 1 -C ₃ ) alkoxy (C 1 -C ₃ ) alkyl define an alkoxyalkyl group having 2 to 6 carbon atoms, these variables are different since the first definition allows both the alkoxy group and the alkyl moiety separately contain 4 or 5 atoms, while the second definition limits the number of atoms in these groups to three.

-4GB 288076 B6

All temperatures are in degrees Celsius.

TLC refers to thin layer chromatography.

THF means tetrahydrofuran.

DMF means dimethylformamide.

DMSO means dimethylsulfoxide.

Brine means a saturated solution of sodium chloride.

IR means infrared spectroscopy.

NMR means nuclear magnetic resonance, chemical shift is reported in ppm (δ) relative to tetramethylsilane.

TMS means tetramethylsilane.

-O means phenyl (C ₆ H ₅ ).

MS means mass spectrometry expressed in m / z or mass / charge units. [M + H] ⁺ means the cation of the parent compound plus a hydrogen atom. El means electron impact ionization. Cl means chemical ionization. FAB means accelerated atom ionization.

HRMS refers to high performance mass spectrometry.

Ether means diethyl ether.

Pharmaceutically acceptable means those properties and / or substances that are acceptable to the patient from a pharmacological-toxicological point of view and for pharmaceutical chemists in the manufacture from a physicochemical point of view such as composition, formulation, stability, patient acceptance and bioavailability.

Pharmaceutically acceptable salts include salts of the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic, CH ₃ - (CH 2) _n i-COOH, where _n 1 is zero to 4, HOOC- (CH 2) _n i-COOH, wherein n 1 is the same as defined above, HOOC-CH = CH-COOH, O-COOH.

When a mixture of two solvents is used, the solvent ratio is expressed as volume / volume (v / v) ratio.

When solid solubility is used, it is indicated by weight / volume (m / v) ratio.

DETAILED DESCRIPTION OF THE INVENTION

Without further elaboration, it is believed that one skilled in the art can utilize the present disclosure and utilize the invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and / or perform the various processes of the invention and are presented as illustrative and not exhaustive of the invention in any way. One skilled in the art will readily recognize appropriate variations of both reactants and reaction conditions and techniques.

-5GB 288076 B6

Example 1

9- [2- (Methanesulfonyloxy) ethyl] -2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole II

9- [2- (Hydroxy) ethyl] -2,4-di-1-pyrrolidinyl-9 H -pyrimido [4,5- b] indole (I, J. Med. Chem., 38, 4161-3 (1995)) is reacted with methanesulfonyl chloride in a manner known to those skilled in the art to produce the desired compound.

Example 2 1 - [(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetyl] pyrrolidine monohydrochloride, also known as pyrrolidinamide acid 2,4-di- 1-pyrrolidinyl-9H-pyrido [4,5-b] indol-9-yl) acetic acid IV / V

A stirred mixture of 9- [2- (methanesulfonyloxy) ethyl] -2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole (II, Example 1 and WO / 9626941-A1, 165 g), sodium cyanide (180 g), water (360 mL) and DMSO (3000 mL) were heated at 100 ° C for 18 hours. It is important that the methanesulfonate feed contains triethylamine traces either as a residue after its preparation or added intentionally. The mixture is cooled to 20 ° C to 25 ° C, dissolved in water (approximately 6000 mL) and filtered. The solid residue is washed with water to remove excess cyanides, then rubbed with acetone. Filtration and drying gave 2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole III, mp 209-211 ° C; NMR (CDCl ₃ ) 7.88, 7.22, 7.09, 3.95.3.67, and 1.98 δ; MS (m / z, FAB, M + H) 308;

The mixture obtained 2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole (III, 93.1 g) in THF (2150 mL) was cooled to -40 ° C and reacted over 30 min. minutes with n-butyllithium / hexane (1.6 M, 246 mL). After 30 minutes, a mixture of bromoacetylpyrrolidine [J. Copper. Chem., 30, 20-24 (1987), 93.1 g] in THF (750 mL) and allowed to react for 15 minutes. The reaction mixture is then warmed to 20-25 ° C for two hours and then recooled to -40 ° C and filtered. The solid residue is partitioned between dichloromethane and water, the organic layer is dried and concentrated to give the free base of the title compound, compound IV, mp = 201-204 ° C; NMR (CDCl ₃ ) 7.87, 7.38, 7.21-7.08, 05.05, 3.92, 3.62, 3.48, 3.33, 1.96 and 1.85 δ.

Treatment of the free base of the title compound in methanol with one equivalent of methanolic hydrochloric acid affords the title compound V, mp = 250-255 ° C; MS (m / z, M + is observed) = 418.2476, calculated for C ₂₄ H ₃₀ N ₆ O = 418.2481. (The salt component, in this case the hydrochloride, did not show up in MS, which is normal.)

Example 3

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid, pyrrolidinamide sulphate

The basic procedure of the last paragraph of Example 2 is followed, with variations that are not essential, but (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole-9- yl) acetic acid (IV, Example 2.) and sulfuric acid. Melting point = 175-180 ° C.

-6GB 288076 B6

Example 4

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid pyrrolidinamide methanesulfonic acid salt

The basic procedure of the last paragraph of Example 2 is followed with variations that are not essential, but (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5b] indol-9-yl) acetic acid is used as the starting material. , pyrrolidinamide (IV, Example 2.) and methanesulfonic acid. This gives the title compound of example, m.p. = 199-200 ° C.

Example 5

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9yl) acetic acid pyrrolidinamide phosphate salt

The basic procedure of the last paragraph of Example 2 is followed, with variations that are not essential, but (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5b] indol-9-yl) acetic acid is used as starting material. , pyrrolidinamide (IV, Example 2) and phosphoric acid. This gives the title compound of example, m.p. = 200 - 201 ° C.

Example 7 (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid t-butyl ester IV

N-Butyllithium (4.26 mL; 1.6 M in hexane) was added to a mixture of 2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole (III, Example 2, 2.0) g) in THF (50 mL) at -15 ° C. After one hour, t-butyl bromoacetate (1.27 g) in THF (20 mL) was added and the mixture was stirred at 20-25 ° C for two hours. The mixture was then fractionated between aqueous sodium carbonate solution and dichloromethane, the organic layer was dried and concentrated. Chromatography of the crude product (silica gel; hexane / dimethyl chloride / ethyl acetate (70/25/5)) gives the title compound, m.p. = 131-133 ° C; NMR (CDCl 3) 7.87, 7.15, 4.92, 3.92, 3.61, 1.96 and 1.43 δ; MS (m / z) = 421 (M < + >).

Example 8

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid hydrochloride VII

A mixture of (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid t-butyl ester, t-butyl ester (VI, Example 7, 2.5 g) in aqueous hydrochloric acid (1.0 M) is heated to reflux for two hours. The mixture is then cooled and concentrated to approximately one third of the original volume. Filtration of the resulting solid gave the title compound, mp 250-253 ° C; NMR (CDCl 3) 8.07, 7.35, 5.21, 4.10, 3.73 and 2.11 δ; IR (neat) 2925, 1736, 1627, 1608, 1568, 1445 and 1193 cm ^-1 .

Example 9

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid morpholinamide IV and its monohydrochloride V

A mixture of (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid hydrochloride (VII, Example 8, 1.41 g) in dichloromethane (20 mL) was added. was treated with triethylamine (1.08 mL) with cooling to -5 ° C, then treated with isobutyl chloroformate (0.5 mL). The mixture was stirred for

The reaction mixture was then treated with morpholine (0.83 ml). The mixture was stirred for two hours and then subjected to fractionation between dichloromethane and aqueous sodium carbonate solution. The layers are separated and the organic layer is concentrated after drying, the residue is purified by chromatography (silica gel; acetone / dichloromethane, 10/90) to give the free base of the title product, mp 220-222 ° C.

A mixture of the free base IV of the title compound (1.3 g) in methanol (50 mL) was treated with an equivalent of methanolic hydrochloric acid. Recrystallization of the resulting solid from methanol / ethyl acetate gave the title compound, m.p. = 238-240 ° C; NMR (CH 3 OD) 8.0, 7.42, 7.35, 7.27, 5.31.3.98, 380.3.69, 3.59 and 2.06 δ.

Example 10

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 2-aminomethylpyridinamide, IV and its dihydrochloride V

Use the base of Example 9 with variations that are not essential but use 2- (aminomethyl) pyridine instead of morpholine and two equivalents of hydrochloric acid to form the salt to give the free base IV of the title compound, converting it to the desired title compound, temperature mp = 162-165 ° C; NMR (CH 3 OD) 8.77, 8.58, 8.00, 7.47, 7.30, 5.33, 4.81, 4.10, 3.74, and 2.12.

Example 11

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid amide IV and its hydrochloride V

The basic procedure of Example 9 was followed with variations of no significant significance but using ammonia instead of morpholine to give the free base IV of the title compound, converting it to the title compound, m.p. = 260-264 ° C; NMR (CH 3 OD) 8.06, 7.36, 5.12, 4.05, 3.67 and 2.08 δ.

Example 12

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9yl) acetic acid 1-amino-1-deoxysorbitolamide IV and its hydrochloride V

The basic procedure of Example 9 was followed, with variations of no particular importance but using 1-amino-1-deoxysorbitol instead of morpholine to give the free base (IV) of the title compound, converting it to the desired title compound, m.p. 126 [deg.] C .; MS (m / z) calculated = 529.2774, observed 529.2779.

Example 13

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid prolylamide IV and its hydrochloride V

The base of Example 9 was used with variations that were not essential, but proline was used instead of morpholine to give the free base IV of the title compound, which was converted to the desired title compound, m.p. = 118-120 ° C; MS (m / z) calculated = 462.2379, observed 462.2371.

-8EN 288076 B6

Example 14

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid glycinamide, IV and its hydrochloride V

The basic procedure of Example 9 was followed with variations of no significant importance but using glycine instead of morpholine to give the free base IV of the title compound, converting it to the desired title compound, m.p. = 155-160 ° C; NMR (CH ₃ OD) 8.04, 7.47, 7.37, 7.29, 5.17.4.00, 3.66, 3.30 and 2.08 δ.

Example 15

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid hydroxylaminamide, IV and its hydrochloride V

The basic procedure of Example 9 was followed with variations of no significant importance but using O-benzylhydroxylamine instead of morpholine to give the free base IV of the title compound, converting it to the O-benzyl derivative of the title compound, mp = 184-186 ° C . This material (523 mg) is debenzylated by hydrogenation in the presence of palladium on carbon (10%, 504 mg), DMF (50 mL), hydrogen (310 kPa for 5.5 hours). Filtration and concentration of the filtrate gave the free base IV of the title compound, m.p. = 147-150 ° C. Formation of the hydrochloride was carried out according to the procedure of Example 9 to give the title compound, m.p. = 210-212 ° C; MS (m / z) calc 381.2039, found 381.2028.

Example 16

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 3-hydroxypyrrolidinamide, IV and its salt V

The basic procedure of Example 9 was followed with variations of no significant importance, but using 3-hydroxypyrrolidine instead of morpholine to give the free base IV of the title compound, converting it to the desired title compound, mp - 224-226 ° C; MS (m / z) = 431.1 (M +), as for its hydrochloride, m.p. = 145-150 ° C.

Example 17

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 4-amino-1-butanolamide IV and its hydrochloride V

The basic procedure of Example 9 was followed with variations of no significant importance but using 4-amino-1-butanol instead of morpholine to give the free base (IV) of the title compound, m.p. = 199-201 ° C, converted to salt of the title compound, m.p. = 108-110 ° C; MS (m / z) = calc. 436.2587, found 436.2574.

Example 18

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 4-aminobutanamide, IV

The basic procedure of Example 9 was followed with variations of no significant importance but using 4-aminobutanoic acid in place of morpholine to give the title compound, mp = 215-220 ° C, MS (m / z) = 450, 2379, measured 450.2379.

-9EN 288076 B6

Example 19

(2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 2-hydroxypyrrolidinamide, IV

The basic procedure of Example 9 was followed, with variations not essential, but using 4-aminobutanol diethyl acetal instead of morpholine to give the acetal intermediate, m.p. = 153-156 ° C. The acetal is subsequently hydrolyzed by the procedure of J. Org. Chem., 48, 3667 (1983). A mixture of acetal intermediate (103 mg), sodium iodide (80 mg) and trichloromethylsilane (0.05 ml) in acetonitrile (2 ml) was stirred at 20-25 ° C for 30 minutes. The reaction mixture is then fractionated between aqueous sodium carbonate, sodium thiosulfate and dichloromethane, the layers are separated and the organic layer is concentrated after drying. Chromatography of the concentration residue (silica gel; acetone / dichloromethane, 10/90) gives the desired title compound (its free base), m.p. = 185-190 ° C; MS (m / z) = calcd 434.2430; measured 434.2421. NMR (CDCl ₃ ) 7.87, 7.65, 7.26, 7.16, 5.47, 5.28, 4.88, 4.84, 4.79, 3.93, 3.66-3 , 61 and 1.99-1.91 5.

Test of the usefulness of the compounds of the invention in the treatment of asthma

Currently, asthma in humans is known as chronic eosinophilic inflammatory airway disease. The utility of the compounds of the invention was tested. The test has been published, see AM. J. Physiol 273 (Lung Cell. Mol. Pysysiol. 17) L513-L523 (1997). Simulated asthmatic eosinophilic pulmonary inflammation was developed in animal models (mice). Methylprednisolone is very active in this assay and is taken as a standard. The compounds of the invention have been shown to be orally effective inhibitors of antigen-induced eosinophil accumulation in susceptible rodents, as shown in Table 1.

Table 1

-10GB 288076 B6

PNU-170199A 6105-9 CH, 9 · Ηα 0 3.0 28 PNU-170480E 6105-10 I \ · 2HCI 3.0 1.0 3.0 10.0 54 -7 2 7 ll JL I) O PNU-170481A 6105-11 / X · H · ^N ii - 0 k _c .o 1 NHj 3.0 30

-11EN 288076 B6

PNU-170483A 6105-12 / \ · Ha > OH OH OH OH 3.0 1.0 3.0 10.0 85 29 44 47 PNU-170483A 6105-13 I \ 7Γ · HCI ^{N <} il --- k JOLO O y ““ Y) 3.0 1.0 3.0 10.0 83 54 54 81 PNU-170484A 6105-14 / \ Sr · HCI ^N ΊΊ ------ aJL jo o ° 1 ^^ COOH 3.0 3.0 1 -32

-12GB 288076 B6

PNU-170578A 6105-15 cr Q ά • HCl X A ° 1 H ^X OH 3.0 3.0 49 41 PNU-171519 1.0 77 6105-16 O N 3,0 10,0 82 91 X) .alpha OH PNU-171586A 3.0 23 «105-17 \ r HCl ? il - A ° ) N z H

-13GB 288076 B6

PNU-172185 6105-18 f ~~ \ XX N O i O N II ^H ΌΗ 1.0 3.0 10.0 28 -9 29 PNU-172231 6105-19 / \ ^{N <} il --- il ^ il Al JU 0 P HO 1.0 3.0 10.0 41 5 37

Comparison of usefulness and toxicity of some prior art compounds and compounds of the invention

From the results shown in Table 2 below, it is evident that the compounds of the invention do not exhibit in vitro toxicity as determined by measuring lactate dehydrogenase activity in the culture medium of gall bladder epithelial cells and rat hepatocytes. In contrast, the prior art compounds AYER-194 of WO93 / 20078, JACKETS-5, JACKETS-8, JACKETS-10, JACKETS-26 of WO96 / 26941 are toxic and therefore not useful in the treatment of asthma despite their usefulness in this treatment. Compounds 10 of WO96 / 26941 containing a cyclic amine exhibit toxicity. Surprisingly and unexpectedly, the compounds of WO93 / 20078 and WO96 / 26941 show liver, bile duct and / or gallbladder toxicity, while the compounds of the invention do not show toxicity.

-14GB 288076 B6

Table 2

compound aromatic r ₇ Useful in the treatment of asthma toxicity AYER-12 No -ch ₃ + none AYER-138 Yes -ch ₃ + none AYER-194 No _{-CH2 -CH2} morpholinyl + toxic JACKETS-3 Yes _{-CH2 -CH2} -OH - none JACKETS-5 Yes -CH 2 -CH 2 -piperidinyl + toxic JACKETS-8 Yes -CH ₂ -CH ₂ -imidazolyl + toxic JACKETS-10 Yes _{-CH2 -CH2} morpholinyl + toxic JACKETS-26 Yes -H + toxic 6105-2 Yes -CH 2 -CO-pyrrolidinyl +++ none 6105-9 Yes -CH 2 -CO-morpholinyl + none 6105-10 Yes -CH 2 -CO-NH-CH 2 -pyridin-2-yl + none 6105-11 Yes -CH 2 -CO-NH ₂ + none 6105-12 Yes -CH ₂ CO-NH-CH 2 - (CH (OH) 4) -CH ₂ OH + none 6105-13 Yes -CH ₂ -CO-proline + none 6105-14 Yes -CH 2 -CO-glycine + none 6105-15 Yes -CH ₂ -CO-NH-OH + none 6105-16 Yes -CH ₂ -CO- (3-hydroxypynlidine) metabolite none 6105-17 Yes -CH ₂ -CO- (4-amino-1-butanol) metabolite none 6105-18 Yes -CH 2 -CO- (4-aminobutanoic acid) metabolite none 6105-19 Yes -CH 2 -CO- (2-hydroxypyrrolidone) metabolite none

+ means useful in the treatment of asthma

- means useless for the treatment of asthma

-15GB 288076 B6

Scheme A

(ΠΙ)

-16GB 288076 B6

(ΙΠ)

-17GB 288076 B6

Scheme C

(IH)

(VI)

(VII)

^R s-2 (IV)

-18GB 288076 B6

Claims (12)

PATENT CLAIMS Tricyclic amines of the general formula IV wherein R 1 and R 2 are linked to a nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidyl and 4-morpholinyl; R ₂ and R ₂ are linked to a nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidyl and 4-morpholinyl, wherein the heterocyclic ring R 1 / R 1 'is same as R ₂ _! / _ ₂ R _2; n 1 is 1 to 3; R3-1 is: (1) -H (2) C 1 -C ₃ alkyl (3) -phenyl; R3-2 (1) -H (2) -CH ₂ - [2-pyridinyl], (3) -CH ₂ - [3-pyridinyl], (4) _--CH2 - [4-pyridinyl], (5) -CH ₂ - [CH (OH)] ₄ CH ₂ -OH, (7) -CH ₂ -COOH, (8) -OH, (9) -CH ₁ -CH ₂ -CH ₂ -CH ₂ OH, (10) -CH ₂ - CH ₂ -CH ₂ -CO-OH, or _R3 and R3-1 _ ₂ are connected with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of (1) 1-pyrrolidinyl, (2) 1-piperidyl, (3) 4-morpholinyl, (4) 2-hydroxy-1-pyrrolidinyl, (5) 3-hydroxy-1-pyrrolidinyl, (6) 1-prolyl, and pharmaceutically acceptable salts thereof. The tricyclic amines of the general formula IV according to claim 1, wherein R _{1 -} / R _{1 - 2} , and R _{2 -} / R _{2 - 2} are linked to the nitrogen atom to which they are attached to form 1-pyrrolidinyl. 3. A compound according to claim 1 wherein nj is 1. The tricyclic amines of formula IV according to claim 1, wherein R ₃ is -H a R ₃ -2 is selected from the group consisting of (1) -H, (2) -CH ₂ - [2-pyridyl], (5) -CH ₂ - [CH (OH)] 4 CH ₂ -OH, (7) - CH-COOH, (8) -OH, (9) -CH-CH-CH-CH-OH (10) -CH-CH-CH-COOH, and wherein R ₃ and R ₃ _i _ ₂ are joined with a nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of (1) 1-pyrrolidinyl, (2) 1-piperidyl, (3) 4-morpholinyl, (4) 2-hydroxy-1-pyrrolidinyl (5) 3-hydroxy-1-pyrrolidinyl, (6) 1-prolyl, and pharmaceutically acceptable salts thereof. The tricyclic amines of the general formula IV according to claim 4, wherein R _{3 -} and R _{3 - 2} are linked to the nitrogen atom to which they are attached to form 1-pyrrolidinyl. The tricyclic amines of formula IV according to claim 4, wherein the pharmaceutically acceptable salts are selected from the group consisting of hydrochloride, sulfate, methanesulfonate, maleate and phosphate. The tricyclic amines of claim 1, selected from the group consisting of (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid, pyrrolidinamide (2) 4-di-1-pyrrolidinyl-9H-pyrido [4,5-b] indol-9-yl) acetic acid, (2,4-di-1-pyrrolidinyl-9H-pyrimido) 2-aminomethyl-pyridinamide-9H-pyrimido [4,5-b] indol-9-yl) -acetic acid (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9yl) acetic acid, [4,5-b] indol-9-yl) acetic acid, 1-amino-1-deoxysorbitolamide, (20-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid, (2,4-di-1-pyaolidinyl-9H-) -propolylamide pyrido [4,5-b] indol-9-yl) acetic acid, (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid hydroxylamine, (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid, 3-hydroxypyrrolidinamide, (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 4-amino-1-butanolamide, (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 4-aminobutanamide, (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid 2-hydroxypyrrolidinamide. 8. The compound of claim 7 which is (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid pyrrolidinamide. The tricyclic amines of claim 7, which are selected from (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid pyrrolidinamide monohydrochloride, (2,4- di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid methanesulfonic acid salt of (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indole) (9-yl) acetic acid, (2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9yl) acetic acid maleic salt, and (2,4-di- 1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid. (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid t-butyl ester as an intermediate for the preparation of tricyclic amines of formula IV according to claim 1. (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid and its pharmaceutically acceptable salts as intermediates for the preparation of tricyclic amines of formula IV according to claim 1. (2,4-Di-1-pyrrolidinyl-9H-pyrimido [4,5-b] indol-9-yl) acetic acid hydrochloride according to claim 11 as an intermediate for the preparation of tricyclic amines of general formula IV according to claim 1.